NOVEL SYNTHESIS OF QUINOLINE-5,8-DIONE ANALOGUES
A THESIS
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE
MASTER OF SCIENCE
BY
ALICEN M. TEITGEN
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NOVEL SYNTHESIS OF
QUINOLINE-5,8-DIONE ANALOGUES
A THESIS
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT FOR THE REQUIREMENTS
FOR THE DEGREE
MASTER OF SCIENCE
BY
ALICEN M. TEITGEN
ADVISOR: DR. ROBERT E. SAMMELSON
BALL STATE UNIVERSITY
MUNCIE, INDIANA
JULY 2012
Acknowledgements
I would like to thank the Ball State Chemistry department for allowing me the
opportunity to earn my Masters degree. To the faculty who I’ve been given the chance to
get know, I’ve learned a lot from each of you and enjoyed getting to know you. I would
like to express my deep gratitude to Dr. Robert Sammelson for allowing me the
opportunity to work with him on this research project. I greatly appreciate your patience
with all my questions, insight into my research and dedication to the subject. I thoroughly
enjoyed sharing our love for chemistry and running. Also, I would like to thank Dr. Philip
Albiniak and Dr. James Poole for all your guidance and education. All three of you have
challenged and pushed me and for that I will be forever grateful.
I would like to thank all my friends and family. To my fellow classmates, thank
you for the sharing your challenges, excitements and talents with me. To my friends, who
play such a special role in my life, thank you for always encouraging me to fulfill my
dreams. And my family, who have always gone the extra mile to love and support me, I
could not have done this without you.
I wish to express my deepest thanks and appreciation to my wonderful husband
Jake. Thank you for listening during the frustrating times of research and keeping me
company on my long drives from Noblesville. Thank you for encouraging me to pursue
my vocation and for always believing in me.
I feel truly blessed to have all of you in my life!
Abstract
Thesis: Novel Synthesis of Quinoline-5,8-Dione Analogues
Student: Alicen Teitgen
Degree: Master of Science
College: Sciences and Humanities
Date: July 2012
Pages: 92
The chemistry of quinonline-5,8-dione as a functional group is a developing field
because of its various biological aspects. Lavendamycin and streptonigrin are known
antibiotic, antitumor agents containing the quinolone-5,8-dione functional group believed
to provide their antitumor properties. Most cancer cells show an elevated level of NQO1
enzyme which activates lavendamycin to act as an antitumor agent. The research goal is
to explore different synthetic methods and reactions to produce novel quinolone-5,8dione analogues with unique structural features while keeping the selective cytotoxicity.
Lavendamycin contains a β-carboline and streptonigrin has a substituted pyridine
connected to the 2-position of the quinolone-5,8-dione. The overall goal of this project
will develop synthetic methods to create 1,2,3-triazoles and 1,2-diazoles attached to the
quinoline moiety from azides and diazonium salts, respectively.
In order to accomplish this, 8-hydroxyquinoline undergoes through a four step
synthesis to install an azide at the two position of the quinoline ring. 8-Hydroxyquinoline
was oxidized to produce 8-hydroxyquinoline-N-oxide, converted into 8-acetoxy-2hydroxyquinoline with acetic anhydride, reacted with POCl3 to produce 2-chloro-8hydroxyquinoline, and treated with sodium azide to form 2-azido-8-hydroxyquinoline.
However it was found that the product cyclized to yield 8-hydroxy-tetrazole[1,5a]quinoline.
In the quinoline-5,8-dione synthesis, 7-amidoquinoline-5,8-dione is prepared
through a three step synthesis. 8-Hydroxquinoline was nitrated to form 8-hydroxy-5,7dinitroquinoline, hydrogenated/acylated to give 5,7-diacetamido-8-acetoxyquinoline, and
oxidized to yield 7-acetamidoquinoline-5,8-dione. In order to reach the end of this
project, the four step tetrazole and the three step quinoline-5,8-dione syntheses required
merging. Further research will focus on the optimization of these syntheses.
Table of Contents
Page Number
ii
iii
iv
List of Figures
List of Schemes
List of Tables
Chapter 1
Introduction and Background Literature
1.1 Introduction
1.2 Quinoline-5,8-dione
1.3 NQO1 Enzyme
1.4 Synthesis of Lavendamycin Analogues
Chapter 2
Synthesis of 8-Hydroxy-Tetrazole[1,5-a]quinoline
2.1 Introduction
2.2 Literature Methods
2.3 Results and Discussion
2.4 Experimental
2.5 Data
Chapter 3
20
20
22
26
29
Synthesis of 7-Amino-Quionoline-5,8-Dione
3.1 Introduction
3.2 Literature Methods
3.3 Results and Discussion
3.4 Experimental
3.5 Data
Chapter 4
2
3
5
8
33
33
36
39
41
Novel Synthesis of Quinoline-5,8-Dione Analogues
4.1 Introduction
4.2 Results and Discussion
4.3 Experimental
4.4 Data
45
45
51
53
Appendix
57
ii
List of Figures
Page Number
Chapter 1
Introduction and Background Literature
Figure
1 Structure of Quinoline-5,8-Dione
2 Structure of Mitomycin, Doxorubicin and Daunomycin
3 Structures of Lavendmaycin and Streptonigrin
4 The Binding Site of NQO1 Enzyme
5 Quinoline-5,8-Dione
6 Retrosynthesis of Lavendamycin Core
7 Compounds synthesized using Pd(O) cross-coupling
8 Synthesis of Lavendmaycin Analogues by Pictet-Spengler
Condensation
Chapter 2
Synthesis of 8-Hydroxy-tetrazole[1,5-a]quinoline
Figure
9 Tautomerization of 2,8-Dihydroxyquinoline and
8-Hydroxyquinolinone
Chapter 3
Synthesis of 7-Aminoquinoline-5,8-dione
Chapter 4
Synthesis of Quinoline-5,8-dione Analogues
10 Attempted Synthesis of 8-Hydroxy-5,7-dinitroquinoline-N-oxide
3
4
5
6
8
12
13
14
23
46
iii
List of Schemes
Page Number
Chapter 1
Introduction and Background Literature
Scheme
1 Kende and Ebetino’s Synthesis of Lavendamycin Methyl Ester
2 Boger’s Synthesis of Lavendamycin
3 Ciufoline’s Synthesis of Lavendamycin
Chapter 2
Synthesis of 8-Hydroxy-tetrazole[1,5-a]quinoline
Scheme
4 Sigouin’s Synthesis of 2-Chloro-8-hydroxyquinoline
5 Storz’s Synthesis of 2-Amino-8-hydroxyquinoline
6 Modified Procedure for Making 2-Chloro-8-hydroxyquinoline
7 Synthesis of 8-Hydroxy-tetrazole[1,5-a] from
2-Chloro-8-hydroxyquinoline
8 Synthesis of 2-Amino-8-hydroxyquinoline
Chapter 3
Synthesis of 7-Aminoquinoline-5,8-dione
Scheme
9 Synthesis of 7-Aminoquinoline-5,8-dione through Bromination
10 Synthesis of quinoline-5,8-dione after Cross-Coupling Reaction
11 Behforouz’s Synthesis of Quinoline-5,8-dione
12 Synthesis of 7-Bromoquinoline-5,8-dione
13 Different Route for the Synthesis of 2-Aminoquinoline-5,8-dione
14 Synthesis of 7-Acetamidoquinoline-5,8-dione
Chapter 4
Synthesis of Quinoline-5,8-dione Analogues
Scheme
15 Nitration Reaction and Products
16 Synthesis of 7-Acetamido-tetrazole[1,5-a]quinoline-5,8-dione
17 Synthesis of 7-Bromo-tetrazole[1,5-a]quinoline-5,8-dione
9
10
11
20
21
23
24
24
33
34
35
36
37
37
47
48
50
iv
List of Tables
Page Number
Chapter 1
Introduction and Background Literature
Table
1 Metabolism of Lavendamycin Analogues
2 In Vitro Cytotoxicity of Lavendamycin Analogues
Chapter 2
Synthesis of 8-Hydroxy-tetrazole[1,5-a]quinoline
Chapter 3
Synthesis of 7-Aminoquinoline-5,8-dione
Chapter 4
Synthesis of Quinoline-5,8-dione Analogues
16
17
Chapter 1
Introduction and
Background Literature
1.1
1.2
1.3
1.4
Background
Quinoline-5,8-dione
NQO1 Enzyme
Synthesis of Lavendamycin Analogues
2
1.1
Background
In the United States today, cancer accounts for nearly one quarter of recorded
deaths per year, a total exceeded only by heart disease.1 In the year 2012, more than a
half a million people will die from cancer, an average of about 1,500 people per day.1
Fortunately, various organic compounds are being identified and/or synthesized as
possible antitumor agents. To understand how these compounds combat tumors, it is
important to identify the critical aspects of cancerous cells.
Cancer consists of a large group of diseases characterized by uncontrolled growth
and spread of abnormal cells.1 Both external factors such as tobacco, radiation and
chemicals and internal factors like inherited mutations, immune conditions and hormones
can be the causes of cancer.2 Whether cancerous or noncancerous, cells go through the
cell cycle to reproduce. Normal cells stop dividing when they come into contact with like
cells, this mechanism is known as contact inhibition.2 However, cancerous cells lack these
checks and balances and lose the ability to limit cell division. Chemotherapy, a common
cancer treatment, is effective because it halts cell division altogether. This is usually
achieved by damaging either the cellular RNA or DNA, which directs the cell to copy
itself during division and prevention of this process causes cell death.2
Chemotherapy drugs are most effective at killing cells that are rapidly dividing. 2
Unfortunately, most of our current chemotherapy drugs cannot distinguish between
cancerous cells and normal cells. “Normal cells” will eventually repopulate, but several
side effects can occur during treatment including low blood counts, mouth sores, nausea,
diarrhea and hair loss.2 Different chemotherapy drugs may affect various parts of the
3
body. Currently, researchers are looking into developing drugs that are selectively toxic
to cancer cells.
1.2
Quinoline-5,8-Dione
One area of drug research being develop is based on compounds containing a
quinoline-5,8-dione functional group (1) shown in Figure 1. The quinoline-5,8-dione
moeity has several important biological functions including antifungal, antibacterial,
antriparasitic and antitumor activity.3
Figure 1: Structure of Quinoline-5,8-dione
Mitomycin C (2) is an example of a chemotherapy drug, specifically a quinone
antitumor antibiotic shown in Figure 2.4 The mitomycins are a family of aziridinecontaining natural products isolated from Streptomyces lavendulae.4 Mitomycin C (2) is
given as an injection and is used in the treatment of adenocarcinoma of the stomach and
pancreas, anal, bladder, breast, cervical and small-celled lung cancer.4 It acts during
multiple phases of the cell cycle as a DNA crosslinker. Specifically, mitomycin C is
activated by the reduction of the quinone followed by alkylation of the aziridine with the
guanine nucleoside in DNA strands which blocks DNA replication and thus causes cell
death.4
4
Figure 2: Structures of Mitomycin C, Doxorubicin and Daunomycin
Another quinone antitumor antibiotic isolated from Streptomyces lavendulae is
Doxorubicin (3), which is closely related to the natural product daunomycin (4) both
shown in Figure 2.5 Doxorubicin is given by intravenous injection (IV) and, similar to
mitomycin C, is used to treat several types of cancer.5 Doxorubicin is considered a cell
cycle-specific drug because it acts during multiple phases of the cell cycle. The planar
aromatic part interacts by intercalating itself between DNA base pairs not allowing the
double helix to reseal, stopping DNA replication and causing cell death.5
Ongoing research is being done on other quinone antitumor antibiotics, including
the compound lavendamycin (5). This compound was first isolated from the fermentation
broth of Streptomyces lavendulae in 1981 by Balitz while the structure was determined
by Doyle.6,7 The structure of 5 is pentacyclic and includes two moieties, a quinoline-5,8dione and a β-carboline.7 Several methods were used to determine the structure, including
elemental analysis, infrared, ultraviolet absorption (UV), mass spectroscopy and nuclear
magnetic resonance (NMR).7
5
Figure 3: Structures of Lavendamycin and Streptonigrin
Lavendamycin (5) is related in structure to streptonigrin (6) and plays a similar
role as an antitumor agent (Figure 3).6,7 Streptonigrin was isolated in 1959 from
Streptomyces flocculus and has shown to inhibit several human tumors.8 No single
mechanism has been determined as the cause for streptonigrin toxicity towards cells.
There are indications that the quinoline-5,8-dione is essential for the antitumor activity.3
However, streptonigrin is a very potent bone marrow depressant, and therefore it is
prohibited for clinical use.9 Because of the similarity structure, researchers became
interested in studying lavendamycin. Like streptonigrin, lavendamycin and lavendamycin
methyl ester (7) have shown antitumor properties, but their toxicity concerns continue to
delay clinical application.
1.3
NQO1 Enzyme
It is believed that the quinoline-5,8-dione is the essential functional group in
lavendamycin for cytotoxic activity because it is activated by NAD(P)H:quinone
oxidoreductase 1 (NQO1). NQO1 is a homodimeric flavoenzyme composed of two
associated monomers of 273 residues.10 Each residue contains a FAD cofactor molecule
6
that is required for NQO1 catalytic activity.10 At the NQO1 active site, quinone substrates
can bind in more than one orientation as shown below in Figure 4.10 Figure 4a and 4b
show a lavendamycin analogue binding to the FAD cofactor in two different orientations.
Figure 4c shows the molecular surface of the NQO1 active site. The active site is a
hydrophobic and plastic pocket with three potential hydrogen-bonding residues including
Tyrptophan-126, Tryptophan-128 and Histidine-161.10 The quinone substrate binds at the
active site, but the functional group coming off the β-carboline can effect binding affinity
of lavendamycin analogues.
b
a
c
Figure 4: The Binding Site of NQO1 Enzyme10
7
The goal of current cancer drug discovery is to design cytotoxic compounds that
selectively interact with tumor cells with minimal toxicity to normal cells. Many tumor
cells show elevated levels of the NQO1 enzyme.10 Reports have shown higher levels of
NQO1 activity in lung, liver, colon and breast tumors.10 Ideally, antitumor compounds
that are bioactivated by NQO1 like lavendamycin could be selectively toxic to those
tumors.
For lavendamycin when the quinoline-5,8-dione binds to the activation site, the
quinolinedione undergoes a two electron reduction.10 In the first step of the reaction a
hydride ion from NAD(P)H is transferred to the FAD followed by the release of
NAD(P)+.10 In the second step of the reaction, FADH2 donates the hydride to either a
carbonyl oxygen or ring carbon followed by the hydroquinone release.10 The other proton
is donated by either Tyr-126, Tyr-128 or His-161.10 The two-electron reduction is known
as a ping-pong mechanism.10 However, the exact mechanism of how cell death occurs is
still being determined. Research has rationalized that it could be due to the depletion of
NADPH/NADH, the uncoupling of oxidative phosphorylation, and/or the single-strand
cleavage of DNA.11
Several syntheses of the quinoline-5,8-dione moiety have provided a variety of
substituted derivatives at the C-6 and/or C-7 position (Figure 5).3 Some of the C-6 and
C-7 substituents include amino, hydroxyl, thiol, alkyl, halogen and nitro groups. 3 Many
biological studies have encompassed substituents at the C-6 and C-7 position. Studies
have shown that small substitutes at the 7-postion of lavendamycin analogues are less
hindered with the internal wall of the NQO1 active site.3 As for the C2 and C3 position,
most analogues included small substituents on the C2 position and no substituents at the
8
C3 position.10 Substrates having an aziridine ring or methyl group at C2 have been
reported as good substrates of NQO1.10
Figure 5: Quinoline-5,8-Dione
1.4
Synthesis of Lavendamycin Analogues
In 1984, Kende and Ebetino reported the first synthesis of lavendamycin methyl
ester (7) in a total of nine steps with an overall yield of 2% (Scheme 1).11,12 They
synthesized this compound by the promoted condensation of 7-bromo-5-nitro-8methoxyquinaldic acid (8) with β-methyltryptophan methyl ester (9) to give the
corresponding amide 10. Tryptophanamide 10 was converted to the β-carboline ester 11
via a Bischler-Napieralski type condensation.11 The Bishler-Napieralski reaction cyclizes
the tryptophan amide to a β-carboline ester through an intramolecular electrophilic
aromatic substitution. Compound 11 was reduced to 12. With the core in place, 12 was
oxidized with potassium dichromate to form the quinone (13), which was then reacted
with sodium azide and reduced to produce lavendamycin methyl ester (7).11
9
Scheme 1: Kende and Ebetino’s Synthesis of Lavendamycin Methyl Ester
In the same year, Boger reported a total synthesis of lavendamycin methyl ester in 20
steps with an overall yield of ~0.5% (Scheme 2).13 Their method was based on a
Friedlander condensation of 2-amino-3-benzyloxy-4-bromobenzaldehyde (14). The
aminoaldehyde was reacted with the β-carboline, 1-acetyl-3-(methoxycarbonyl)-4methyl-β-carboline (15) to the build B-ring (16) and provided the complete carbon
skeleton of lavendamycin. Debenzylation of 16 gave 8-hydroxyquinoline derivative 17,
10
which was then oxidized to quinone 18. Conversion of 18 to lavendamycin methyl ester
(7) was accomplished in two steps similar to the work of Kende.13
Scheme 2: Boger’s Synthesis of Lavendamycin
In 1993, Ciufoline used an approach modified from the Knoevenagel-Stobbe
pyridine formation shown in Scheme 3.14 Condensation of quinoline 19 with 2azidobenzaldehyde (20) provided chalcone 21.14 This enone was reacted with 2ethoxybut-1-ene and 2-ethoxybut-2-ene to form 22.14 The formation of the pyridine (23)
occurred from the reflux of 23 with hydroxylamine hydrochloride in acetonitrile.14
Compound 23 was oxidized to form 24 and thermolysis produced the β-carboline 25.14
This gave the framework for lavendamycin. Aldehyde 25 was oxidized and then
11
converted to 26.14
This was the same intermediate as Boger, which was treated
identically to yield lavendamycin methyl ester (7).14
Scheme 3: Ciufoline’s Synthesis of Lavendamycin
12
More recently, Albert Padwa and Mohammad Behforouz have independently
explored at different ways of synthesizing new lavendamycin analogues. Padwa and his
research group have been working on using heteroaryl cross-coupling as a method to
synthesize new compounds. They looked at a retrosynthesis of a much simpler N-acetyl
analogue of lavendamycin shown below in Figure 6.15 They concluded they could obtain
the skeletal framework from a Pd(0)-catalyzed cross-coupling reaction.15
Figure 6: Retrosynthetic Pathway for Lavendamycin Core
Padwa’s group worked on synthesizing lavendamycin analogues from two key
intermediates, 2-stannyl-5,7-dinitro-8-alkoxyquinoline with 2-halopyridine.15 Figure 7
shows several compounds synthesized from the Pd(0)-catalyzed cross-coupling reaction.
Their methods never actually obtained true lavendamycin analogues.
13
Figure 7: Compounds Synthesized Using Pd(0)-Catalyzed Cross-Coupling
In 2010, Behforouz reported a study of the biological activities of 25 different
lavendamycin analogues.12 The compounds were synthesized through Pictet-Spengler
condensation of the quinolinedione aldehydes with tryptophans as shown in Figure 8.12
The quinolinedione aldehydes were prepared through a several step synthesis from 8hydroxy-2-methylquinoline. Also, several of the tryptophans were synthesized from
commercially available compounds. Six of the twenty-five analogues were amino
lavendamycins and they were prepared by the acid hydrolysis of the corresponding 7acylamino lavendamycin. The 25 compounds are listed in Tables 1 and 2. 12
14
Figure 8: Synthesis of Lavendamycin Analogous by Pictet-Spengler Condensation
Behforouz studied two biological aspects of the analogues, including metabolism
and in vitro cytotoxicity. Metabolism was measured by looking at the reduction rates of
lavendamycin by NQO1.12 The concentration was measured in mol/min/mg, and the
higher the rate, the better the metabolism. In vitro cytotoxicity was determined by the
ratio of cell survival of NQO1 deficient cells versus NQO1 rich cells. The concentrations
of cell survival were measured in M. Then the ratio was calculated from the
concentrations and the higher the ratio, the better the selectivity.
12
The results of the
biological studies are shown in Tables 1 and 2.
Entry 20 in Tables 1 with the amino group at the R1 position and the morpholino
group at the R3 position had the highest metabolism rate in the presences of NQO1. Also,
15
entry 20 in Table 2 had the highest selectivity ratio of cell survival of NQO1 deficient
cells versus cell survival of NQO1 rich cells compared to the other lavendamycin
analogues.12 This could be due to the amino group being a small substituent with limited
steric hinderance within the NQO1 active site.11 Also, morpholino could have its oxygen
contribute to hydrogen bonding in the active site which would increase the binding
affinity to the active site.12 The interaction would allow this analogue to be in a good
position to accept the hydride ion from FAD and reduce the quinone.12
16
Table 1: Metabolism of Lavendamycin Analogues
Entry
R1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3(CH2)2CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
(CH3) 2CHCO
HCO
ClCH2CO
ClCH2CO
2-Furyl-CO
HO2C(CH2) 2CO
H
H
H
H
H
H
H
R2
R3
H
N[(CH2CH2) 2]O
H
O(CH2) 2CH(CH3) 2
H
OCH3
H
N[(CH2) 4]
H
NH(CH2) 2OH
H
OCH3
H
OCH(CH3)CH2CH3
H NHCH2CH(OH)CH2OH
H
O(CH2)CH3
H N[(CH2CH2) 2]NCH2Ph
H
OCH2CH3
H
OCH2CH3
H
OCH3
H
OCH3
H
NH2
H
N[(CH2) 4]
H
OCH3
H
OC4H9-n
Cl
OCH2CH3
H
N[(CH2CH2) 2]O
H
O(CH2) 2CH(CH3) 2
H
OCH3
H
N[(CH2) 4]
H
NH(CH2) 2OH
H
OCH3
R4
R5
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
OH
OH
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
OH
OH
H
H
H
Metabolism
(mol/min/mg)
43 ± 7
2.2 ± 0.7
3.9 ± 2.0
36 ± 6
6.8 ± 3.5
8.7 ± 1.5
3.6 ± 0.3
21 ± 6
0.04 ± 0.08
20 ± 8
13 ± 2
34 ± 5
5.8 ± 1.7
5.2 ± 2.6
6.9 ± 1.1
103 ± 8
2.9 ± 1.4
31 ± 7
35 ± 7
26 ± 4
28 ± 2
17
Table 2: In Vitro Cytotoxicity of Lavendamycin Analogues
Entry
R1
R2
R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3(CH2)2CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
(CH3) 2CHCO
HCO
ClCH2CO
ClCH2CO
2-Furyl-CO
HO2C(CH2) 2CO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
N[(CH2CH2) 2]O
O(CH2) 2CH(CH3) 2
OCH3
N[(CH2) 4]
NH(CH2) 2OH
OCH3
OCH(CH3)CH2CH3
NHCH2CH(OH)CH2OH
O(CH2)CH3
N[(CH2CH2) 2]NCH2Ph
OCH2CH3
OCH2CH3
OCH3
OCH3
NH2
N[(CH2) 4]
OCH3
OC4H9-n
OCH2CH3
N[(CH2CH2) 2]O
O(CH2) 2CH(CH3) 2
OCH3
N[(CH2) 4]
NH(CH2) 2OH
OCH3
R4
R5
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
OH
OH
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
OH
OH
H
H
H
Selectivity
ratio
BE/BE-NQ
2.1
0.8
›2.8
1.3
0.7
1.3
0.8
1.4
2.1
2.7
1.6
9.0
2.5
›1.1
1.0
2.0
18
The overall goal of our project was to synthesize new quinoline-5,8-dione
analogues. Keeping in mind what previous research has been done, we wanted to change
the functionality at the 2-postion of 8-hydroxyquinoline, which would yield new
quinoline-5,8-dione analogues and new lavendamycin analogues. Most lavendamycin
analogues that have been synthesized have a β-carboline at the 2-position of the
quinoline-5,8-dione. Changing the 2-substituent to an azide or an amino could yield new
lavendamycin analogues with a 1,2,3-triazole or 1,2-diazole heterocycle instead of a
pyridine ring. These new derivatives are much different in structure from the β-carboline
of lavendamycin analogues that have been synthesized in the past thirty years. The hope
is the new moieties will be reactive with the NQO1 enzyme, have a low toxicity profile
and therefore giving a greater chance of using these lavendamycin analogues for clinical
trials.
Chapter 2
Synthesis of 8-Hydroxytetrazole[1,5-a]quinoline
2.1
2.2
2.3
2.4
2.5
Introduction
Literature
Results and Discussion
Experimental
Data
20
2.1
Introduction
The first goal of this research was to place a functional group at the 2-position of
the quinoline ring that would allow for the synthesis of 2-azido-8-hydroxyquinoline. The
two routes explored involved making 2-chloro-8-hydroxyquinoline and 2-amino-8hydroxyquinoline in hopes either could be treated with sodium azide to yield 2-azido-8hydroxyquinoline. The chloro derivative would undergo nucleophilic aromatic
substitution and the amino analogue through the corresponding diazonium ion.
2.2
Literature Methods
Previous syntheses have been reported for 2-chloro-8-hydroxyquinoline (31) and
2-amino-8-hydroxyquinoline (32). Sigouin and Beauchamp synthesized 2-chloro-8hydroxyquinoline from 8-hydroxyquinoline, shown in Scheme 4.16
Scheme 4: Sigouin’s Synthesis of 2-Chloro-8-hydroxyquinoline
8-Hydroxyquinoline (27) was oxidized to make 8-hydroxyquinoline-N-oxide (28), which
was then acetylated to give 8-acetoxy-2-hydroxyquinoline (29). Next, 29 was reacted
with methanol and potassium carbonate before being acidified with 10% HCl to isolate
21
2,8-dihydroxyquinoline (30). Finally, 30 was treated with phosphorous oxychloride to
make 2-chloro-8-hydroxyquinoline (31).
Storz published a safe and practical synthesis of 2-amino-8-hydroxyquinoline (32,
Scheme 5).17 The first step was again synthesizing 8-hydroxyquinoline-N-oxide (28)
from 8-hydroxyquinoline (27), however, Storz used a 39% solution of peracetic acid.
Compound 28 was methylated with 1 equivalent of dimethyl sulfate, heated at reflux and
then left to stir at room temperature overnight. The solution was slowly added to cold
ammonium hydroxide and 2-amino-8-hydroxyquinoline (32) precipitated out of solution.
Scheme 5: Storz’s Synthesis of 2-Amino-8-hydroxyquinoline
There are no previous literature-reported methods of substituting 2-chloro-8hydroxyquinoline to yield 2-azido-8-hydroxyquinoline. A literature method of converting
2-chloroquinoline-N-oxide
to
2-azidoquinoline-N-oxide
has
been
reported
by
Abramovitch.18 2-Chloro-quinoline-N-oxide and sodium azide were dissolved in a
solution of hydrochloric acid, water and acetone. The reaction was left to stir for 72 h at
room temperature. The solid that precipitated out of solution was collected and
chromatographed on basic alumina to yield 2-azidoquinoline-N-oxide.
Similar to the 2-chloro-8-hydroxyquinoline, there are no published procedures for
converting 2-amino-8-hydroxyquinoline to 2-azido-8-hydroxyquinoline. Boyer and
Soliman published similar procedures using 2-aminopyridine. Both methods used sodium
nitrite to make a diazonium salt, which was then treated with sodium azide to yield the
22
corresponding 2-azidopyridine. The goal was to use 2-amino-8-hydroxyquinoline to
produce 2-azido-8-hydroxyquinoline following either one of the methods.19,20
2.3
Results and Discussion
The method developed by Sigouin and Beauchamp was followed through with an
overall yield of 11%. However, the procedure was modified in many places to shorten the
synthesis and give a higher percent yield. First, we looked at different ways of making
the 8-hydroxyquinoline-N-oxide (28). To synthesize 28, Storz’s method using a peracetic
acid solution was explored and gave a yield of 61%; whereas Sigouin and Beauchamp’s
method which used acetic acid and 30% hydrogen peroxide to make peracetic acid
afforded 57% yield. Also, another method was tried which combined aspects of the two
processes. In this case, 8-hydroxyquinoline was dissolved in glacial acetic acid and 30%
hydrogen peroxide and then heated to reflux overnight. After cooling, instead of adding
ammonium hydroxide, the solution was extracted using the steps outlined in Storz’s
procedure. This yielded 26% of the N-oxide compound. After attempting all three
procedures, using a peracetic acid solution to make the N-oxide gave a better percent
yield, and when used in the next steps of making 2-chloro-8-hydroxyquinoline, the
overall percent yield was 20%.
The second part of the procedure that was modified was making 2-chloro-8hydroxyquinoline (31) from 30. This method was followed as written and provided a
56% yield. However, it was also found that this step could be skipped and 8-acetoxy-2hydroxyquinoline (29) could be directly converted to 2-chloro-8-hydroxyquinoline (31)
with a 52% yield. The overall yield was almost identical, but helped to shorten the
23
synthesis. The new synthesis for making 2-chloro-8-hydroxyquinoline is shown in
Scheme 6.
Scheme 6: Modified Procedure for Making 2-Chloro-8-hydroxyquinoline
Lastly, we reported 30 as 8-hydroxy-2(1H)quinolinone instead of 2,8-dihydroxyquinoline
to comply with most examples in the literature. This is acceptable because the
dihydroxyquinoline tautomerizes to form the quinolinone as shown in Figure 9.
Figure 9: Tautomerization of 2,8-Dihydroxyquinoline and 8-Hydroxy2(1H)quinolinone
Abramovitch’s method was modified to make 2-azido-8-hydroxyquinoline as
shown in Scheme 7. We found that the azide does substitute for the chloro at the 2
position, but the product cyclizes to form a tetrazole. This was confirmed from an IR
spectrum of our new compound. An azide stretch should absorb around 2100 cm-1, but
the product spectrum showed no absorbance in this band. It was concluded that the
24
tetrazole is likely hydrogen bonding to the hydroxyl group at the 8 position because of
the sharp OH peak on both the IR and 1H NMR spectra. Comparing our data to previous
work done showed the azide and the tetrazole are in equilibrium favoring the tetrazole
form.21 Thus, we concluded 8-hydroxy-tetrazole[1,5-a]quinoline (33) is even more
favored with the hydrogen bonding.
Scheme 7: Synthesis of 8-hydroxy-tetrazole[1,5-a]quinoline from 2-Chloro-8hydroxyquinoline
Storz’s procedure for synthesizing 2-amino-8-hydroxyquinoline (31) was a 212 g
scale pilot experiment.17 However, we needed to scale it down for our use. The second
step converting the N-oxide to the amino compound seemed to be sensitive and needed to
be monitored carefully in order to complete the reaction. The synthesis of 2-amino-8hydroxyquinoline (32) is shown in Scheme 8. 1H NMR and
13
C NMR matched the
reported spectra and further purification was not warranted.
Scheme 8: Synthesis of 2-Amino-8-hydroxyquinoline
Two different methods to convert 2-amino-8-hydroxyquinoline (32) to 8-hydroxytetrazole[1,5-a]quinoline (33) were explored. The first method dissolved the amino
25
compound in 25% H2SO4 and cooled to 0 °C. Then a solution of sodium nitrite was
added dropwise and the mixture was left to stir for 30 min to complete the diazotization.
A solution of sodium azide was added slowly. Finally, solid sodium bicarbonate was
added to make the mixture basic and the solid was collected by vacuum filtration.
The second method dissolved the amine (32) in 12 M HCl and ice. A solution of
sodium nitrite was added dropwise and then a solution of sodium azide was added
slowly. Saturated sodium bicarbonate was used to neutralize the reaction and the solid
was collected by vacuum filtration. In both methods, only starting material was
recovered.
A third method of making 8-hydroxy-tetrazole[1,5-a]quinoline (33) directly from
the N-oxide in a similar way the 2-amino-8-hydroxyquinoline was made. The N-oxide
was treated the same with acetonitrile and dimethyl sulfate, but, after stirring overnight, a
solution of sodium azide was used instead of ammonium hydroxide. However, no product
precipitated out of solution. So, instead of dissolving sodium azide into an aqueous
solution, solid sodium azide was used. After the addition of the 8-hydroxy-1methoxyquinolinium solution, solid sodium azide was undissolved in solution so water
was added until it did dissolve. It was stirred at room temperature over 72 h, but no
precipitate ever viable product was ever formed. Therefore, it was concluded the best
way
to
make
hydroxyquionline.
8-hydroxy-tetrazole[1,5a]quinoline
was
substituting
2-chloro-8-
26
2.4
Experimental
8-Hydroxyquinoline-N-oxide (28) (Method 1)
8-Hydroxyquinoline (8.02 g, 55.2 mmol) was dissolved in glacial acetic acid (50
mL) and 30% hydrogen peroxide (20 mL). Once the solid had dissolved, the solution was
heated at reflux (70 ˚C) overnight. After cooling to room temperature, the pH was
adjusted to 12 with ammonium hydroxide. The brown solid (4.97 g, 56%) was collected
by vacuum filtration.
8-Hydroxyquinoline-N-oxide (28) (Method 2)
8-Hydroxyquinoline (10.61 g, 72.9 mmol) was dissolved in of DCM (110 mL).
32% Peracetic acid (15.5 mL, 73.6 mmol) was cooled to 5 ˚C and added dropwise to the
solution. The solution was stirred at room temperature for 3 hours, and then quenched
with a solution of saturated sodium thiosulfate (2.76 g, 17.5 mmol) in 4.5 mL of H2O.
The organic phase was extracted with 1 M HCl (2 x 37.5 mL), saturated aqueous
NaHCO3 (42.5 mL), saturated aqueous Na2CO3 (10.5 mL), and brine (20 mL). The
organic layer was evaporated under reduced pressure to give a crude solid. To purify, 25
mL of DI water was added to the solid, stirred a room temperature of 30 min, and filtered.
The wet solid was washed with 25 mL of toluene and filtered again and dried to give a
light orange solid (6.86 g, 61%)
8-Acetoxy-2-hydroxyquinoline (29)
8-Hydroxyquinoline-N-oxide (2.00 g, 12.4 mmol) was dissolved in acetic
anhydride (25 mL, 260 mmol). The mixture was heated at reflux (140 ˚C) for 5 hours.
The mixture was cooled and then the solvent was removed under reduced pressure giving
27
a tan solid. The crude solid was washed with ethanol and collected by vacuum filtration
(1.39 g, 61%).
8-Hydroxy-2(1H)quinolinone (30)
8-Acetoxy-2-hydroxyquinoline (0.90 g, 4.4 mmol) was dissolved in methanol and
potassium carbonate (0.61 g, 4.4 mmol) was added. The mixture stirred at room
temperature for 1 hour. Then the solvent was removed under reduced pressure. The
brown solid was dissolved in 15 mL of DI water and a 10% HCl solution was slowly
added. The tan solid that precipitated out was collected by vacuum filtration (0.70 g,
97%).
2-Chloro-8-hydroxyquinoline (31) (Method 1)
5,8-Dihydroxyquinoline (1.05 g, 6.5 mmol) were dissolved in POCl3 (8 mL, 85.8
mmol) and heated over a steam bath for 1 hour. The mixture was slowly transferred into a
mixture of 56.3 g of ice and 28 mL of 28% ammonium hydroxide. The solid was
collected by vacuum filtration and dissolved in 56 mL of HCl which was heated on a
steam bath for 1 hour. A Na2CO3 solution (1.8 mol/L, 150 mL) was added to the solution.
Then a dark gray solid was filtered. The dark solid was dissolved in methanol and DI
water was added to cloudiness. The solution was placed in the freezer for 3 hours.
Vacuum filtration was used to collect the brown solid (0.65 g, 56%)
2-Chloro-8-hydroxyquinoline (31) (Method 2)
Similar
procedure
followed
from
above
to
scale
with
8-acetoxy-2-
hydroxyquinoline (1.45 g, 7.1 mmol) yielded a light brown solid (0.67 g, 52%)
2-Amino-8-hydroxyquinoline (32)
28
8-Hydroxyquinoline-N-oxide (0.93 g, 5.8 mmol) was dissolved in dry acetonitrile
(5 mL) which was heated to reflux. The dry acetonitrile was obtained through distillation.
After the mixture reached reflux, dimethyl sulfate (0.55 mL, 5.8 mmol) was slowly added
over 30 min. The mixture refluxed for 11 hours and then stirred at room temperature
overnight. In a separate flask, of 28% ammonium hydroxide (1.5 mL, 10.9 mmol) was
cooled to -20 ˚C with a mixture of acetonitrile and liquid nitrogen. Then the mixture was
slowly added to the 28% ammonium hydroxide. After stirring for an hour, 28%
ammonium hydroxide (0.5 mL, 3.6 mmol) was added to the cool solution. Then the
reaction stirred for 1.5 hours at 10 ˚C before a dark brown solid was collected by
filtration (0.61 g, 66%)
8-Hydroxy-tetrazole[1,5-a]quinoline (33)
2-Chloro-8-hydroxyquinoline (0.45 g, 2.5 mmol) was placed in a roundbottomed
flask with sodium azide (0.5 g, 7.7 mmol), 0.25 mL of 12 M HCl in 12.5 mL of water
and 25 mL of acetone. The reaction was left to stir at room temp for 72 h. Solvent was
removed under reduced pressure until solid precipitated out of solution. A white solid
was collected by vacuum filtration which was purified with column chromatography on
silica gel with chloroform. The collections were monitored by TLC. The first fractions
collected were the starting material and the solvent was removed to give a cream colored
solid. The second fractions collect were the azide product. The solvent was removed
under reduced pressure to yield a white solid (0.24 g, 52%)
29
2.5
Data
8-Hydroxyquinoline-N-oxide (28)17
1
H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 5.7 and 0.8 Hz, 1H), 8.08 (d, J = 8.8 Hz,
1H), 7.57-7.47 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 1.1 and 8.1 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6) δ 153.9, 136.0, 132.6, 131.0, 130.7, 129.3, 122.3, 117.6,
114.6.
8-Acetoxy-2-hydroxyquinoline (29)16
1
H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.43 (dd, J = 8.1
and 1.1 Hz, 1H), 7.34 (dd, J = 8.1 and 1.1 Hz, 1H), 7.19 (dd, J = 8.1 Hz, 1H), 6.65 (d, J =
9.5 Hz, 1H).
13
C NMR (100 MHz, CDCl3) δ 169.2, 163.4, 140.6, 137.0, 131.2, 125.3,
123.6, 122.5, 122.1, 121.3, 21.4.
8-Hydroxy-2(1H)quinolinone (30)16
1
H-NMR (400 MHz, CD3OD-d4) δ 7.93 (d, J = 9.5 Hz, 1H), 7.14 (dd, J = 7.7 and 1.5 Hz,
1H), 7.08 (dd, J = 7.7 Hz, 1H), 6.99 (dd, J = 7.7 and 1.5 Hz, 1H), 6.60 (d, J = 9.5 Hz,
30
1H). 13C NMR (100 MHz, CD3OD-d4) δ 163.4, 144.2, 142.0, 127.6, 123.0, 121.0, 120.2,
118.3, 114.4.
2-Chloro-8-hydroxyquinoline (31)16
1
H-NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.66 (br s, 1H), 7.46 (t, J = 7.7
Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 7.7 and 1.1 Hz,
1H).
13
C NMR (75 MHz, CDCl3) δ 151.4, 149.1, 139.1, 137.9, 128.2, 127.2, 123.1,
118.0, 111.8.
2-Amino-8-hydroxyquinoline (32)17
1
H-NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 7.8 and 1.1 Hz,
1H), 7.02 (dd, J = 7.6 Hz, 1H), 6.91 (dd, J = 7.3 and 1.1 Hz), 6.82 (d, J = 9.1 Hz, 1H),
6.64 (br s, 2H).
13
C NMR (100 MHz, DMSO-d6) δ 157.4, 150.4, 137.8, 137.5, 123.5,
122.3, 118.3, 113.3, 111.5.
8-Hydroxy-tetrazole[1,5-a]quinoline (33)
mp 168-170 ˚C. IR (ATR): 3339, 3035, 1615, 1540, 1573, 817 cm-1. 1H-NMR (400 MHz,
CDCl3) δ 9.48 (br s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.62 (dd, J =
31
8.1 Hz, 1H), 7.50 (dd, J = 8.1 and 1.1 Hz, 1H), 7.45 (dd, J = 8.1 and 1.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 147.7, 147.3, 134.6, 129.4, 126.0, 119.7, 119.3, 118.2, 112.3.
Chapter 3
Synthesis of 7-Amino
quinoline-5,8-dione
3.1
3.2
3.3
3.4
3.5
Introduction
Literature Methods
Results and Discussion
Experimental
Data
33
3.1
Introduction
With methods in place to functionalize the 2-position of 8-hydroxyqunoline, we
wanted to explore different methods of making the quinoline-5,8-dione. Both Padwa and
Behforouz have published procedures to make quinoline-5,8-dione analogues. Before
trying to convert 2-chloro-8-hydroxyquinoline, 2-amino-8-hydroxyquinoline or 8hydroxy-tetrazole[1,5-a]quinoline into their quinoline-5,8-diones, the most efficient
method for quinone synthesis needed to be determined. Both Padwa’s method and
Behforouz’s method were first attempted with 8-hydroxyquinoline.
3.2
Literature Methods
To synthesize the quinoline-5,8-dione, Padwa’s group looked at two different
methods. The first method used 7-aminoquinolinediones directly as coupling partners as
shown in Scheme 9.15
Scheme 9: Synthesis of 7-Aminoquinoline-5,8-dione through Bromination
34
2-Chloro-8-hydroxyquinoline (31) was brominated to produce 5,7-dibromo-2-chloro-8hydroxyquinoline (34). The 5,8-dione (35) was formed by oxidizing 34. Then sodium
azide was employed to allow the azide to displace the bromo and prepare 7-azido-2chloroquinoline-5,8-dione. This azide was reduced to the corresponding amine (36). The
7-amino-2-chloroquinoline-5,8-dione (36) was produced in low yields. Also, the group
could
not
convert
7-amino-2-chloroquinoline-5,8-dione
36
to
7-amino-2-
stannylquinoline-5,8-dione needed for their cross-coupling reaction.
The second method looked at making the quinoline-5,8-dione after the cross
coupling step. 15 The synthesis is shown in Scheme 10 and is very similar to the method
Behforouz had published in the 1997.
Scheme 10: Synthesis of Quinoline-5,8-dione after Cross-Coupling Reaction
Padwa’s group reduced dinitro compound 37 to diamino compound 38 through
hydrogenation at 30 psi for 15 h. Compound 38 was converted to 5,7-diacetamido-8methoxy-2-(5-methylpyridin-2-yl)quinoline (39)
through acetic anhydride and
35
triethylamine. Finally, a solution of ceric ammonium nitrate (CAN) in water was added to
the mixture of 39 in acetonitrile to make 7-acetamido-2-(5-methylpyridin-2-yl)quinoline5,8-dione (40). In their work, there was no attempt to hydrolyze the acetamide in order to
obtain the amine.
Because of the importance of the 5,8-dione, Behforouz developed a method for
synthesizing the quinoline-5,8-dione more efficiently with a better overall yield. 3 In the
reaction shown in Scheme 11, 8-hydroxy-2-methylquinoline (41) undergoes nitration to
form 8-hydroxy-2-methyl-5,7-dinitroquinoline (42), which was then reduced and acylated
to form 5,7-diacetamido-8-hydroxy-2-methylquinoline (43). Compound 43 was oxidized
to form 7-acetamido-2-methylquinoline-5,8-dione (44), which could undergo hydrolysis
to form the 7-aminoquinoline-5,8-dione (45). An advantage of Behforouz’s method is
that the synthesis is reasonably short with overall high yields and none of the steps
require chromatographic purification.3
Scheme 11: Behforouz’s Synthesis of Quinoline-5,8-dione
36
3.3
Results and Discussion
In Padwa’s method, bromination of 2-chloro-8-hydroxyquinoline was followed by
oxidization to get the quinoline-5,8-dione. Whereas Behforouz’s group nitrated 2-methyl8-hydoxyquinoline, reduced and acetylated the nitro groups and then oxidized. Both
options were explored to see which procedure worked best for our target compounds.
When working through Padwa’s method, the first two steps were completed as shown in
Scheme 12. 8-Hydroxyquinoline (27) was brominated to form 5,7-dibromo-8hydroxyquinoline (46) and then oxidized to form 7-bromoquinoline-5,8-dione (47).
However, the last step could not completed of making 7-aminoquionline-5,8-dione. The
first step converts 47 to 7-azidoquinoline-5,8-dione followed an immediate reduction to
48. When the triphenylphosphine was added to reduce the azide, no nitrogen gas was
observed implying the azide was not present. Therefore, a different route was attempted
to make 7-azidoquinoline-5,8-dione.
Scheme 12: Synthesis of 7-Bromoquinoline-5,8-dione
37
When making 8-hydroxy-tetrazole[1,5-a]quinoline (33), a chloride was substituted for an
azide at the 2-position. So 7-azidoquinoline-5,8-dione was attempted to be sythensized
from 7-bromoquinoline-5,8-dione (47) using the same procedure (Scheme 13). However,
still no 7-aminoquinoline-5,8-dione was isolated after attempted reduction.
Scheme 13: Different Route for the Synthesis of 2-Aminoquinoline-5,8-dione
Next, Behforouz’s method was attempted converting 8-hydroxyquinoline to 7acetamidoquinoline-5,8-dione shown in Scheme 14.3
Scheme 14: Synthesizing 7-Acetamidoquinoline-5,8-dione
Nitrating
8-hydroxyquinoline
(27)
worked
well
to
produce
8-hydroxy-5,7-
dinitroquinoline (50). In the next step, when trying to reduce the nitro groups and
acetylate, there was difficulty obtaining 5,7-diacetamido-8-acetoxyquinoline (50) to
precipitate out of solution. Isolation of the hydrochloride salt proved the reduction of the
38
nitro groups worked and that the acetylation step was the problem. In Behforouz’s
procedure, the flask was kept cool in an ice bath while adding acetic anhydride, but then
was left to stir at room temperature for 1.5 h. If the flask became too warm, the product
would not precipitate out of solution. Therefore, keeping the flask in an ice bath after
adding acetic anhydride yielded 50.
Behforouz reported being able to oxidize 5,7-diacetamido-8-acetoxy-2methylquinoline to 7-acetamido-2-methylquinoline-5,8-dione (44).3 Also, he found
converting 5,7-diacetamido-8-acetoxy-2-methylquinoline to 5,7-acetamido-8-hydroxy-2methylquinoline (38) and then oxidizing 43 to 44 worked. Similarly, we found that we
could convert either 50 or 51 to the quinoline-5,8-dione (52).
Both Padwa and Behforouz’s methods activate the 7-postion of the quionline ring
in different ways, but both intend to eventually convert it to a primary amine. We decided
to explore oxidizing 8-hydoxyquinoline with potassium nitrosodisulfonate (Fremy’s salt)
to produce quinoline-5,8-dione. Chia published a general procedure for oxidizing several
8-hydroxyquinolines to quinoline-5,8-dione with Fremy’s salt (1 equivalent), potassium
dihydrogen phosphate and water.22 Once the reaction was complete, the solution was
extracted with dichloromethane and the solvent is removed under reduced pressure.
First Chia’s procedure was tried using 8-hydroxy-tetrazole[1,5-a]quinoline to
convert
to
8-hydroxy-tetrazole[1,5-a]quinoline-5,8-dione,
however
only
starting
compound was extracted. Therefore 8-hydroxyquinoline was used to try and oxidize with
Fermy’s salt. The first NMR showed a mixture of product. The reaction was attempted
again, but only starting material was recovered.
39
3.4
Experimental
5,7-Dibromo-8-hydroxyquinoline (46)
8-Hydroxyquinoline (0.40 g, 2.8 mmol) was dissolved in 10 ml MeOH:DCM
(1:1) and sodium bicarbonate (0.71 g, 8.4 mmol) was added. A solution of bromine (1.33
g, 8.4 mmol) in 10 mL MeOH:DCM (1:1) was added dropwise. The mixture was stirred
at room temperature for 30 minutes and quenched with aqueous sodium sulfite (2.0 g in
10 mL of H2O). Next, dichloromethane (50 mL) was added and the solution was filtered.
The filtrate was washed with water and extracted with dichloromethane. The solvent was
removed by reduced pressure which yielded 5,7-dibromo-8-hydroxyquinoline (0.49 g,
59%).
7-Bromoquinoline-5,8-dione (47)
5,7-Dibromo-8-hydroxyquinoline (0.85 g, 2.8 mmol) was dissolved in
concentrated sulfuric acid (2 mL, 37.5 mmol) and the solution was placed in ice bath.
Concentrated nitric acid (0.6 mL, 9.48 mmol) was added slowly. After stirring for 30 min
in an ice bath, the solution was poured over ice and extracted with dichloromethane (5 x
20 mL). The organic layer was dried with MgSO4, filtered and removed under reduced
pressure to give 7-bromoquinoline-5,8-dione (0.49 g, 74%).
8-Hydroxy-5,7-dinitroquinoline (49)
Concentrated sulfuric acid (5 mL, 93.8 mmol) was placed in a 125 mL
Erlenmeyer flask and 8-hydroxyquinoline (3.9 g, 26.9 mmol) was slowly added. The
flask was placed in an ice bath to keep cool. Once the solid was dissolved ice cold nitric
acid (10 mL, 158 mmol) was slowly added over a 30 min time period. After the addition
was complete, the flask was taken out of the ice bath and allowed to stir at room
40
temperature for 1 h. After 1 h, the mixture was slowly poured onto 100 g of ice/water
(1:1). The mixture stirred until all ice was melted and the solid was collected by vacuum
filtration. The solid was then washed with cold DI water (3 x 25 mL) and ethyl ether (3 x
10 mL) to give 8-hydroxy-5,7-dinitroquinoline (3.83 g, 59%).
5,7-Diacetamido-8-acetoxyquinoline (50)
8-Hydroxy-5,7-dinitroquinoline (8.53 g, 35.9 mmol) was placed in a 500 mL
hydrogenator bottle with 2.0 g of 5% Pd/C and a solution of 15 mL of 12 M HCl in 135
mL of H2O. The solution was placed on the hydrogenator for 17 h at 38 PSI. After taking
it off the hydrogenator, the solution was filtered. The red filtrate was collected in a
roundbottom and placed in an ice bath. Sodium sulfite (5 g, 39.7 mmol) and sodium
acetate (10 g, 121.9 mmol) were added to the flask. About 10 mL of water was added to
help dissolve the solid. Acetic anhydride (35 mL, 370 mmol) was added dropwise over an
hour. The roundbottom was kept cool sitting in an ice bath and left to stir for 1.5 h. and
then the solid was collected by vacuum filtration giving 5,7-diacetamido-8acetoxyquinoline (4.94 g, 39%).
5,7-Diacetamido-8-hydroxyquinoline (51)
5,7-diacetamido-8-acetoxyquinoline (2.78 g, 7.9 mmol) was dissolved in 181.5
mL of methanol:H2O (10:1). The mixture was heated to reflux for 30 min. After reflux,
the solvent was removed under reduced pressure to yield 5,7-diacetamido-8hydroxyquinoline (2.40 g, 98%)
7-Acetamidoquinoline-5,8-dione (52)
5,7-diacetamido-8-acetoxyquinoline (0.31 g, 0.88 mmol) was dissolved in 12.2
mL of glacial acetic acid. A solution of potassium chromate (0.88 g, 4.53 mmol) in 11.5
41
mL of water was added to the solution and left to stir overnight. The dark mixture was
extracted with CH2Cl2 (12 x 5 mL). The organic layer was washed with 3% NaHCO3 (2 x
10 mL). The water layer was then washed with DCM (2 x 5 mL). All the organic layers
were combined and the solvent was removed under reduced pressure to afford an orange
solid (0.12 g, 64%).
7-Acetamidoquinoline-5,8-dione (52)
Following in a similar procedure above with 5,7-diacetamido-8-hydoxyquinoline
(2.40 g, 7.8 mmol) yielded 7-acetamidoquinoline-5,8-dione (0.54 g, 32%)
3.5
Data
5,7-Dibromo-8-hydroxyquinoline (46)23
1
H NMR (300 MHz, CDCl3) δ 8.81 (dd, J = 4.1 and 1.4 Hz, 1H), 8.46 (dd, J = 8.5 and 1.4
Hz, 1H), 7.91 (s, 1H), 7.58 (dd, J = 8.5 and 4.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
149.8, 149.3, 138.7, 136.2, 133.9, 126.7, 123.1, 110.2, 103.9.
7-Bromoquinoline-5,8-dione (47)24
42
1
H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J = 4.8 and 1.8 Hz, 1H), 8.36 (dd, J = 8.0 and
1.8 Hz, 1H), 7.88 (dd, J = 8.1 and 4.8 Hz, 1H), 7.81 (s, 1H).
13
C NMR (100 MHz,
DMSO-d6) δ 183.0, 176.6, 154.7, 147.4, 140.7, 139.8, 134.9, 129.5, 128.9
8-Hydroxy-5,7-dinitroquinoline (49)25
1
H NMR (300 MHz, DMSO-d6) δ 9.82 (dd, J = 8.8 and 1.4 Hz, 1H), 9.26 (s, 1H), 8.94
(dd, J = 5.2 and 1.4 Hz, 1H), 8.27 (dd, J = 8.8 and 5.2 Hz, 1H).
13
C NMR (100 MHz,
DMSO-d6) δ 162.3, 142.7, 142.2, 138.1, 131.1, 130.4, 128.2, 127.6, 123.1.
5,7-Diacetamido-8-acetoxyquinoline (50)26
1
H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.86 (s, 1H), 8.85 (dd, J = 4.4 and 1.4
Hz, 1H), 8.40 (dd, J = 8.4 and 1.4 Hz, 1H), 7.50 (dd, J = 8.4 and 4.4 Hz, 1H), 2.43 (s,
1H), 2.19 (d, J = 6.5 Hz, 2H).
13
C (100 MHz, DMSO-d6) δ 169.7, 169.6, 169.5, 151.1,
141.3, 133.8, 132.5, 131.7, 131.4, 121.3, 120.8, 118.5, 24.4, 23.9, 21.7.
5,7-Diacetamido-8-hydroxyquinoline (51)
43
1
H NMR (400 MHz, DMSO-d6) 9.84 (s, 1H), 9.60 (s, 1H), 8.84 (dd, J = 4.0 and 1.1 Hz,
1H), 8.25 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.49 (dd, J = 8.4 and 4.0 Hz, 1H), 2.13 (d, J =
6.24 Hz, 2H).
7-Acetamidoquinoline-5,8-dione (52)26
1
H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 9.01 (dd, J = 4.8 and 1.8 Hz, 1H), 8.33
(dd, J = 8.0 and 1.8 Hz, 1H), 7.86 (dd, J = 8.0 and 4.8 Hz, 1H), 7.74 (s, 1H), 2.26 (s, 3H).
13
C NMR (100 MHz, DMSO-d6) δ 185.4, 179.2, 172.0, 154.4 147.1, 142.9, 134.1, 129.2,
129.1, 115.8, 22.1
Chapter 4
Synthesis of Quinoline-5,8dione Analogues
4.1
4.2
4.3
4.4
Introduction
Results and Discussion
Experimental
Data
45
4.1
Introduction
Now that 8-hydroxyquinolines with different substituents at the 2-position and
quinoline-5,8-dione with a proton at 2-position had been successfully synthesized, the
final goal of the project was to combine these steps in order to synthesize new quinoline5,8-dione analogues.
4.2
Results and Discussion
Taking all the steps to make 7-aminoquinoline-5,8-dione (Compounds 49-52),
each compound was tried individually to make an N-oxide. First, 7-acetamidoquinoline5,8-dione (52) was used with Siguoin’s method of making the N-oxide, but there were
difficulties getting 52 to dissolved in acetic acid and 30% hydrogen peroxide and
therefore 7-aminoquionline-5,8-dione-N-oxide was never produced. Then Storz’s
procedure was attempted using peracetic acid to make the N-oxide. After taking NMR,
there seemed to be a mixture of compounds including starting material. The reaction was
allowed to run longer, but still produced a mixture of compounds. Column
chromatography was used to try and separate the N-oxide from other material, but pure
isolate 7-acetamidoquinoline-5,8-dione-N-oxide was not isolated. Therefore, we
concluded 7-acetamidoquinoline-5,8-dione-N-oxide could not be formed efficiently.
Next, both 5,7-diacetamido-8-acetoxyquinoline (50) and 5,7-diacetamido-8hydroxyquinoline (51) were used to try and convert to their corresponding N-oxides, but
neither compound seemed to dissolve well using either method and thus could not
efficiently yield the N-oxide. Finally, 5,7-dinitro-8-hydroxyquinoline (49) was used and
the green solid was dissolved in acetic acid and 30% peracetic acid. The mixture was
46
heated at reflux overnight. Then ammonium hydroxide was added dropwise until the
mixture reached a pH of 12, and a yellow solid was collected by vacuum filtration. The
NMR suggested 8-hydroxy-5,7-dinitroquinoline-N-oxide was synthesized due to the
chemical shifts of the peaks upfield as shown in Figure 10. However when 8-hydroxy5,7-dinitroquinoline-N-oxide was dissolved in acetic anhydride and heated to reflux to
make 8-acetoxy-2-hydroxy-5,7-dinitroquinoline, the NMR matched that of 8-hydroxy5,7-dinitroquinoline, meaning 8-hydroxy-5,7-dinitroquinoline-N-oxide never actually
formed.
Figure 10: Attempted Synthesis of 8-Hydroxy-5,7-dinitroquinoline-N-oxide
Since an N-oxide could not be made with any of the compounds used to
synthesize 7-acetamidoquinoline-5,8-dione, 2-chloro-8-hydroxyquinoline (31) and 8hydroxy-tetrazole[1,5-a]quinoline (33) were used to try and convert to quinoline-5,8dione analogues. The same procedure to nitrate 8-hydroxyquinoline (27) was followed to
nitrate compounds 31 and 33. Attempting to dinitrate 2-chloro-8-hydroxyquinoline (31)
with the original procedure found some of 31 was only nitrated once. The reaction
47
required longer reaction times to produce good yields of dinitrated product. Allowing the
reaction to run longer was also helpful when nitrating 31. Both 31 and 33 were
successfully nitrated to form 2-chloro-8-hydroxy-5,7-dinitroquinoline (53) and 8hydroxy-5,7-dinitro-tetrazole[1,5-a]quinoline (54). Also, 53 could be converted to 54
through the same method used to convert 2-chloro-8-hydroxquinoline to 8-hydroxytetrazole[1,5-a]quinoline. All the products formed are shown in Scheme 15.
Scheme 15: Nitration Reactions and Products
The next part of the synthesis required the nitrated products to be reduced via
hydrogenation and then acetylated. First, 2-chloro-8-hydroxy-5,7-dinitroquinoline (53)
was used to be reduced and acetylated, but no product precipitated out of solution; a 1H
NMR was taken of the salt to see if the reduction was working. The NMR showed
48
aliphatic hydrogens at 2.0 ppm, and not as many aromatic hydrogens. It appeared the
palladium inserted with the chlorine and reduced the aromatic ring.
Since reducing 53 did not form the desired product, quinoline-5,8-dione was
attempted to be synthesized from 8-hydroxy-5,7-dinitro-tetrazole[1,5-a]quinoline (54) as
shown in Scheme 16.
Scheme 16: Synthesis of 7-Acetamido-tetrazole[1,5-a]quinoline-5,8-dione
Compound 54 was put on the hydrogentator to be reduced to a hydrochloride salt.
The salt was isolated before acetylating with acetic anhydride. Because the hydrochloride
salt derivative’s NMR results were difficult to read, D2O was added to the NMR tubes
and the NMR spectrum was rerun. After comparing the two 1H NMRs, it seemed 5,7diamino-8-hydroxytetrazole[1,5-a]quinoline hydrochloride had formed. Therefore, the
salt was redissolved with water and acetylated. In Behforouz’s procedure, the 8-acetoxy
derivative precipitated out of solution, but for our compound the 8-hydroxy derivative
was collected. The 1H NMR spectrum showed a peak for the hydroxyl proton downfield
at 11 ppm indicating that 5,7-diacetamido-8-hydroxy-tetrazole[1,5-a]quinoline (55) was
49
formed. Because the –OH moiety was not acetylated, compound 55 did not precipitate
out of the mostly water solution and therefore isolating 55 was difficult. The solution was
extracted with ethyl acetate, the solvent was removed by reduced pressure and dried on
the high vacuum. Even after being dried on the high vacuum, there was a large peak at
around 2.1 ppm indicating unreacted acetic anhydride. Despite the acetic anhydride peak,
there seemed to be small peaks indicating compound 55 was formed.
The solid was dissolved in acetic acid and a solution of potassium dichromate was
added to oxide 55 to 7-acetamido-tetrazole[1,5-a]quinoline-5,8-dione (56). The solution
was extracted with dichloromethane and the solvent removed under reduced pressure.
When the NMR was taken, not all of the solid would dissolve in CHLOROFORM-d. So
the solid that did not dissolved was filtered off and a separate NMR was taken in DMSOd6. The NMR in CHLOROFORM-d did not seem to yield any product. The NMR in
DMSO-d6 seemed to be a small amount of purified compound 55. Therefore, 7acetamido-tetrazole[1,5-a]quinoline-5,8-dione (56) was never obtained.
Also, Padwa’s method with 8-hydroxy-tetrazole[1,5-a]quinoline to form another
quinoline-5,8-dione analogue was attempted as shown in Scheme 17.15 8-Hydroxytetrazole[1,5-a]quinoline (33) was brominated to form 5,7-dibromo-8-hydroxytetrazole[1,5-a]quinoline (57). Padwa’s method required substantial adjustment for the
tetrazole compound 33. Once the bromine solution was added, the reaction needed to stir
longer at room temperature. Compound 57 was purified by recrystallization with
methanol. Padwa’s method was also used to synthesize 7-bromo-tetrazole[1,5a]quinoline-5,8-dione (58) by oxidizing 57 with nitric acid in sulfuric acid.15 Yet, the new
IR spectrum showed an azide stretch around 2100 cm-1. Presumably, the tetrazole no
50
longer hydrogen bonding to the hydroxyl group allows the ring to open up, which shifts
the equilibrium towards the 2-azido-7-bromoquinoline-5,8-dione (59).
Scheme 17: Synthesis of 7-Bromo-tetrazole[1,5-a]quinoline-5,8-dione
Our goal was to explore the chemistry of new substituents at the two position of
8-hydroxyquinoline and to make new quinoline-5,8-dione derivatives in order to yield
novel lavendamycin analogues. The derivatives would be unique from previous
analogues because the structure would not have a β-carboline moiety. Our data indicates,
8-hydroxy-tetrazole[1,5-a]quinoline was the best compound to allow a different group
than a pyridyl ring at the 2 position and worked well to then make the quinoline-5,8dione. Behforouz’s method seemed promising in order to yield the quinoline-5,8-dione
from 8-hydroxy-tetrazole[1,5-a]quinoline (33), but 8-hydroxy-tetrazole[1,5-a]quinoline5,8-dione was never isolated. With Padwa’s procedure, 8-hydroxy-tetrazole[1,5a]quinoline (33) was successfully brominated and oxidized to form 7-bromotetrazole[1,5-a]quinoline-5,8-dione (58), which was likely in the open form of 2-azido-7bromo-tetrazole[1,5-a]quinoline-5,8-dione (59) based on IR analysis. The open form
51
would allow future work to be done to yield new derivatives of lavendamycin analogues
that are different from any research done in this field for the past thirty years.
4.3
Experimental
2-Chloro-8-hydroxy-5,7-dinitroquinoline (53)
8-Hydroxy-5,7-dinitroquinoline (1.00 g, 5.54 mmol) was slowly added to cold
sulfuric acid (1 mL, 18.8 mmol). After the solid had dissolved, nitric acid (2 mL, 31.6
mmol) was slowly added. After the addition of nitric acid, the mixture was removed from
the ice bath and allowed to stir a room temperature for 3h. The dark orange solution was
poured over 20 g of ice:water (1:1). The orange solid was collected by vacuum filtration.
Then it was washed with 3 x 5 mL of cold water and 3 x 2 mL of diethyl ether to yield 2chloro-8-hydroxy-5,7-dinitroquinoline (0.98 g, 65%)
8-Hydroxy-5,7-dinitro-tetrazole[1,5-a]quinoline (54)
Similar procedure was followed from above with 8-hydroxy-tetrazole[1,5a]quinoline (0.25 g, 1.34 mmol), sulfuric acid (0.50 mL, 9.38 mmol), nitric acid (1.0 mL,
15.8 mmol), 5 g of ice:water (1:1), 3 x 1 mL of cold water and 3 x 0.5 mL of diethyl ether
to produce 8-hydroxy-5,7-dinitro-tetrazole[1,5-a]quinoline (0.22 g, 59%).
5,7-Diacetamido-8-hydroxy-tetrazole[1,5-a]quinoline (55)
8-Hydroxy-5,7-dinitro-tetrazole[1,5-a]quinoline (0.33 g, 1.18 mmol) was placed
in a 500 mL hydrogenator bottle with 0.2 g of 5% Pd/C and a solution of 15 mL of 12 M
HCl in 135 mL of H2O. The solution was placed on the hydrogenator for 20 h at 37 PSI.
After removing the reaction from the hydrogenator, the mixture was filtered. The filtrate
was collected in a roundbottom and the solvent was removed by reduced pressure. The
52
salt was then dissolved with water and placed in an ice bath. Sodium sulfite (0.29 g, 2.3
mmol) and sodium acetate (0.57 g, 6.9 mmol) were added to the flask. Acetic anhydride
(2.0 mL, 19.6 mmol) was added dropwise. The roundbottom was kept cool sitting in an
ice bath and left to stir for 1.5 h. Then the solid was collected by vacuum filtration giving
5,7-diacetamido-8-hydroxy-tetrazole[1,5-a]quinoline (0.008 g, 2.2%)
5,7-Dibromo-8-hydroxy-tetrazole[1,5-a]quinoline (57)
8-Hydoxy-tetrazole[1,5-a]quinoline (0.16 g, 0.85 mmol) was dissolved in 3.1 mL
of MeOH:DCM (1:1) and NaHCO3 (0.22 g, 2.6 mmol) was added in a single portion. A
solution of Br2 (0.42 g, 2.6 mmol) in 3.1 mL of MeOH:DCM (1:1) was added over 10
minutes. After addition, the solution was allowed to stir for 3 hours at room temperature
and then quenched with aqueous sodium sulfite (2.00 g in 10 mL of water). DCM (15.5
mL) was added and the mixture was filtered. The filtrate was washed with water and then
extracted with DCM. The removal of the solvent under reduced pressure gave an orange
solid, which was then recrystallized in methanol to yield 5,7-dibromo-8-hydroxytetrazole[1,5-a]quinoline (0.070 g, 24%).
2-Azido-7-bromo-quinoline-5,8-dione (59)
5,7-Dibromo-8-hydroxy-tetrazole[1,5-a]quinoline (0.070 g, 0.20 mmol) was
dissolved with concentrated sulfuric acid (0.2 mL, 3.75 mmol) and the solution was
placed in ice bath. Concentrated nitric acid (0.1 mL, 1.6 mmol) was added slowly. After
stirring for 30 minutes in an ice bath, the solution was poured over ice and extracted with
dichloromethane. The organic layer was dried with MgSO4, filtered and removed under
reduced pressure to give 7-bromo-tetrazole[1,5-a]quinoline-5,8-dione (0.011 g, 18%)
53
4.4
Data
2-Chloro-8-hydoxy-5,7-dinitroquinoline (53)15
1
H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 8.8 Hz, 1H), 9.11 (s, 1H), 7.87 (d, J = 9.1
Hz, 1H).
13
C NMR (100 MHz, DMSO-d6) δ 159.4, 150.1, 142.5, 137.0, 132.5, 130.6,
128.1, 125.8, 124.4.
8-Hydroxy-5,7-dinitrotetrazole[1,5-a]quinoline (54)
mp 116 ˚C – 118 ˚C. IR (ATR): 3104, 2137, 1665, 1622, 1579, 1512, 1415 cm-1. 1H
NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 9.9 Hz, 1H), 9.08 (s, 1H), 8.36 (d, J = 9.9 Hz,
1H). 13C NMR (100 MHz, DMSO-d6) δ 160.8, 147.0, 135.2, 130.0, 128.4, 127.1, 124.0,
123.7, 117.5
5,7-Dibromo-8-hydroxy-tetrazole[1,5-a]quinoline (57)
mp >200 ˚C. IR (ATR): 3273, 3073, 1562, 1604, 1562, 1392, 1312 cm-1. 1H NMR (400
MHz, CDCl3) δ 10.34 (s, 1H), 9.35 (d, J = 9.5 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 9.5 Hz,
54
1H)
13
C NMR (100 MHz, CDCl3) δ 147.4, 144.8, 136.0, 134.0, 123.6, 120.2, 113.7,
112.6, 112.1.
2-Azido-7-bromoquinoline-5,8-dione (59)
IR (ATR): 2928, 2142, 1658, 1582 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J =
11.4 Hz, 1H), 7.53 (s, 1H), 7.13 (d, J = 11.4 Hz, 1H).
144.8, 136.0, 134.0, 123.6, 120.2, 113.7, 112.6, 112.1
13
C NMR (DMSO-d6) δ 147.4,
55
References:
1. Zhu, L.; Pickle, L.W.; Ghosh, K.; Naishadham, D.; Portier, K.; Chen, H.S.; Kim, H.J.;
Zou, Z.; Cucinelli, J.; Kohler, B.; Edwards, B.K.; King, J.; Feuer, E.J.; Jemal, A.
Cancer. 2012, 118, 1100-1109.
2. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/doc
ument/acspc-029771.pdf
3. Behforouz, M.; Haddad, J.; Cai, W.; Gu, Z. J. Org. Chem. 1998, 63, 343-346.
4. Crooke, S.T.; Bradner, W.T. Cancer Treatments Review. 2006, 3, 121-139.
5. Saltiel, E.; McGuire, W. West J. Med. 1983, 139, 332-341.
6. Balitz, D.M.; Bush, J.A.; Bradner, W.T.; Doyle, T.W.; O’Herron, F.A.; Nettleton,
D.E. J. of Antibiot. 1982, 35, 259-265.
7. Doyle, T.W.; Balitz, D.M.; Grulich, R.E.; Nettleton, D.E. Tetrahedron Lett. 1981, 22,
4595-4598.
8. Rao, K.V.; Biemann, K.; Woodward, R.B. J. Am Chem Soc. 1963, 85, 2532-2533.
9. Gould, S.J.; Chang, C.C. J. Am. Chem. Soc. 1977, 99, 5496-5497.
10. Hassani, M.; Cai, W.; Holley, D.C.; Lineswala, J.P.; Maharjan, B.R.; Ebrahimian,
G.R.; Seradj, H.; Stocksdale, M.G.; Mohammadi, F.; Marvin, C.C.; Gerdes, J.M.;
Beall, H.D.; Behforouz, M. J. Med. Chem. 2005, 48, 7733-7749.
11. Kende, A.S.; Ebetino, F.H. Tetrahedron Lett. 1984, 25, 923-926.
12. Wen, C.; Hassani, R.K.; Walter, E.D.; Koelsch, K.H.; Seradj, H.; Lineswala, J.P.;
Mirzaei, H.; York, J.; Olang, F.; Sedighi, M.; Lucas, J.S.; Eads, T.J.; Rose, A.S.;
Charkhzarrin, S.; Hermann, N.G.; Beall, H.D.; Behforouz, M. Biorg. Med. Chem.
2010, 18, 1899-1909.
13. Boger, D.L.; Panek, J. S. Tetrahedron Lett. 1984, 25, 3175-3178.
14. Ciufolini, M.A.; Bishop, M.J. J. Chem. Soc., Chem. Commun. 1993, 1463-1464.
15. Verniest, G.; Wang, X.; De Kimpe, N.; Padwa, A. J. Org. Chem. 2010, 75, 424-433.
16. Sigouin, O.; Beauchamp, A.L. Can. J. Chem. 2005, 83, 460-470.
56
17. Storz, T.; Marti, R.; Meier, R.; Nury, P.; Roeder, M.; Zhang, K. Org. Proc. Res. Dev.
2004, 8, 663-665.
18. Abramovitch, R.A.; Cue, B.W. J .Org. Chem. 1980, 45, 5316-5319.
19. Boyer, J. H.; McCane, D.I.; McCarville, W.J.; Tweedie, A.T. J. Am. Chem. Soc.
1953, 75, 5298-5300.
20. Soliman, R. J. Med. Chem. 1979, 22, 321-325.
21. Chattopadhyay, B.; Rivera Vera, C.I.; Chuprakov, S.; Gevorgyan, V. Org. Lett. 2010,
12, 2166-169.
22. Chia, E.W.; Pearce, A.N.; Berridge, M.V.; Larsen, L.; Perry N.B.; Sansom, C.E.;
Godfrey, C.A.; Hanton, L.R.; Lu, G.L.; Walton, M.; Denny, W.A.; Webb, V.L.;
Copp, B.R.; Harpe, J.L. Bioorg. Med. Chem. 2008, 16, 9432-9442.
23. Naskar, S.; Saha, P.; Paira, R.; Hazra, A.; Paira, P.; Mondal, S.; Maity, A.; Sahu,
K.B.; Banerjee, S.; Mondal, N.B. Tetrahedron Let. 2010, 51, 1437-1440.
24. Boger, D.L.; Duff, S.R.; Panek, J.S.; Yasuda, M. J. Org. Chem. 1985, 50, 5782-5789.
25. Borchardt, R.T.; Thakker, D.R.; Warner, V.D.; Mirth, D.B.; Sane, J.N. J. Med. Chem.
1976, 4, 558-60.
26. Kaiya, T.; Kawazoe, Y.; Ono, M.; Tamura, S. Heterocycle. 1988, 27, 645-649.
Appendix
8-hydroxyquinoline-N-oxide (28)
58
8-hydroxyquinoline-N-oxide (28)
59
8-acetoxy-2-hydroxyquinoline (29)
60
8-acetoxy-2-hydroxyquinoline (29)
61
8-acetoxy-2(1H)quinoline (30)
62
8-acetoxy-2(1H)quinoline (30)
63
2-chloro-8-hydroxyquinoline (31)
64
2-chloro-8-hydroxyquinoline (31)
65
2-amino-8-hydroxyquinoline (32)
66
2-amino-8-hydroxyquinoline (32)
67
8-hydroxy-tetrazole[1,5-a]quinoline (33)
68
8-hydroxy-tetrazole[1,5-a]quinoline (33)
69
8-hydroxy-tetrazole[1,5-a]quinoline (33)
70
5,7-dibromo-8-hydroxyquinoline (46)
71
5,7-dibromo-8-hydroxyquinoline (46)
72
7-bromoquinoline-5,8-dione (47)
73
7-bromoquinoline-5,8-dione (47)
74
5,7-dinitro-8hydroxyquinoline (49)
75
5,7-dinitro-8-hydroxyquinoline (49)
76
5,7-diacetamido-8acetoxyquinoline (50)
77
5,7-diacetamido-8-acetoxyquinoline (50)
78
5,7-diacetamido-8-hydroxyquinoline (51)
79
7-acetamidoquinoline-5,8-dione (52)
80
7-acetamidoquinoline-5,8-dione (52)
81
2-chloro-8-hydroxy-5,7dinitroquinoline (53)
82
2-chloro-8-hydroxy-5,7dinitroquinoline (53)
83
8-hydroxy-5,7-dinitrotetrazole[1,5-a]quinoline (54)
84
8-hydroxy-5,7-dinitrotetrazole[1,5-a]quinoline (54)
85
8-hydroxy-5,7-dinitrotetrazole[1,5-a]quinoline (54)
86
5,7-dibromo-8-hydroxytetrazole[1,5-a]quinoline (57)
87
5,7-dibromo-8-hydroxytetrazole[1,5-a]quinoline (57)
88
5,7-dibromo-8-hydroxytetrazole[1,5-a]quinoline (57)
89
2-azido-7bromoquinoline-5,8-dione
(59)
90
2-azido-7bromoquinoline-5,8dione (59)
91
2-azido-7-bromoquinoline5,8-dione (59)
92